Sunitinib treatment in pediatric patients with advanced GIST following failure of imatinib

Janeway, Katherine A.; Albritton, Karen; Abbeele, Annick D. Van den; D’Amato, Gina Z.; Pedrazzoli, Paolo; Siena, Salvatore; Picus, Joel; Butrynski, James E.; Schlemmer, M.; Heinrich, Michael C.; Demetri, George D.

doi:10.1002/pbc.21909

Cited by 142 publications

(93 citation statements)

References 24 publications

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“…Imatinib and sunitinib, small-molecule inhibitors of the mutant KIT and PDGFRA receptor tyrosine kinases, significantly prolong survival in patients with GIST (7,8). However, imatinib is less effective against WT tumors (9, 10), and initial studies suggest that sunitinib only rarely results in objective responses in WT GIST (10,11). Identification of the pathogenetic mechanism in WT GIST will facilitate the identification of drug targets in these tumors.…”

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confidence: 99%

Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations

Janeway

Kim

Lodish

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Carney-Stratakis syndrome, an inherited condition predisposing affected individuals to gastrointestinal stromal tumor (GIST) and paraganglioma, is caused by germline mutations in succinate dehydrogenase (SDH) subunits B, C, or D, leading to dysfunction of complex II of the electron transport chain. We evaluated the role of defective cellular respiration in sporadic GIST lacking mutations in KIT or PDGFRA (WT). Thirty-four patients with WT GIST without a personal or family history of paraganglioma were tested for SDH germline mutations. WT GISTs lacking demonstrable SDH genetic inactivation were evaluated for SDHB expression by immunohistochemistry and Western blotting and for complex II activity. For comparison, SDHB expression was also determined in KIT mutant and neurofibromatosis-1-associated GIST, and complex II activity was also measured in SDH-deficient paraganglioma and KIT mutant GIST; 4 of 34 patients (12%) with WT GIST without a personal or family history of paraganglioma had germline mutations in SDHB or SDHC. WT GISTs lacking somatic mutations or deletions in SDH subunits had either complete loss of or substantial reduction in SDHB protein expression, whereas most KIT mutant GISTs had strong SDHB expression. Complex II activity was substantially decreased in WT GISTs. WT GISTs, particularly those in younger patients, have defects in SDH mitochondrial complex II, and in a subset of these patients, GIST seems to arise from germline-inactivating SDH mutations. Testing for germline mutations in SDH is recommended in patients with WT GIST. These findings highlight a potential central role of SDH dysregulation in WT GIST oncogenesis.genetic predisposition | sarcoma | pediatric

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confidence: 99%

Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations

Janeway

Kim

Lodish

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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560

475

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“…4) [103,104]. Эти препараты так-же могут быть более активны, чем иматиниб, при ле-чении ГИСО дикого типа [107,108]. Все указанные препараты прошли тестирование в терапии 1-й линии либо в комбинированной те-рапии с иматинибом в рандомизированных иссле-дованиях у больных ГИСО [104].…”

Section: том 2 обзорные статьи 35unclassified

“…ГИСО может быть наследуемым заболеванием: в некоторых семьях с высокой частотой ГИСО выяв-лены герминальные мутации [15]. Встречаются ГИСО и у детей [16].…”

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Molecular features and genetic markers of gastrointestinal stromal tumors

Мазуренко¹,

Цыганова²

2015

Usp. mol. onkol

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“…In addition, sunitinib is beneficial for exon 9 mutated-GIST [97]. Wild-type patients do not seem to benefit from adjuvant imatinib [47]; however, in vivo studies evaluating sunitinib [98] and in vitro studies for nilotinib and dasatinib [79] are promising. As for PDGFRA-mutated GIST, PDGFRA exon 18 generally benefits from adjuvant imatinib therapy, with the exception of PDGFRA exon 18 D842V-mutated GIST [44].…”

Section: Adjuvant Therapymentioning

confidence: 99%

Gastrointestinal Stromal Tumors

Schaefer¹,

Goerres²

2008

Cancer Imaging

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Sunitinib treatment in pediatric patients with advanced GIST following failure of imatinib

Abstract: Sunitinib treatment was associated with substantial initial antitumor activity and acceptable tolerability in this group of pediatric patients with imatinib-resistant GIST.

Cited by 142 publications

References 24 publications

Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations

Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations

Molecular features and genetic markers of gastrointestinal stromal tumors

Gastrointestinal Stromal Tumors

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